Whole-genome transfer raises questions about evolution, sequencing
Friday, 31 August 2007
Scientists at the University of Rochester and the J. Craig Venter Institute have discovered a copy of the entire genome of a bacterial parasite residing inside the genome of its host species.
The finding, reported in today’s Science, suggests that lateral gene transfer — the movement of genes between unrelated species — may happen much more frequently between bacteria and multicellular organisms than scientists previously believed, posing dramatic implications for evolution.
Such large — scale heritable gene transfers may allow species to acquire new genes and functions extremely quickly, says Jack Werren, a principle investigator of the study.
The results also have serious repercussions for genome — sequencing projects. Bacterial DNA is routinely discarded when scientists are assembling invertebrate genomes, yet these genes may very well be part of the organism’s genome, and might even be responsible for functioning traits.
“This study establishes the widespread occurrence and high frequency of a process that we would have dismissed as science fiction until just a few years ago,” says W. Ford Doolittle, Canada Research Chair in Comparative Microbial Genomics at Dalhousie University, who is not connected to the study.
“This is stunning evidence for increased frequency of gene transfer.”
“It didn’t seem possible at first,” says Werren, professor of biology at the University of Rochester and a world — leading authority on the parasite, called Wolbachia.
“This parasite has implanted itself inside the cells of 70 percent of the world’s invertebrates, coevolving with them. And now, we’ve found at least one species where the parasite’s entire or nearly entire genome has been absorbed and integrated into the host’s. The host’s genes actually hold the coding information for a completely separate species.”
Wolbachia may be the most prolific parasite in the world — a “pandemic,” as Werren calls it. The bacterium invades a member of a species, most often an insect, and eventually makes its way into the host’s eggs or sperm. Once there, the Wolbachia is ensured passage to the next generation of its host, and any genetic exchanges between it and the host also are much more likely to be passed on.
Since Wolbachia typically live within the reproductive organs of their hosts, Werren reasoned that gene exchanges between the two would frequently pass on to subsequent generations. Based on this and an earlier discovery of a Wolbachia gene in a beetle by the Fukatsu team at the University of Tokyo, Japan, the researchers in Werren’s lab and collaborators at J. Craig Venter Institute (JCVI) decided to systematically screen invertebrates. Julie Dunning-Hotopp at JCVI found evidence that some of the Wolbachia genes seemed to be fused to the genes of the fruit fly, Drosophila ananassae, as if they were part of the same genome.
Michael Clark, a research associate at Rochester then brought a colony of ananassae into Werren’s lab to look into the mystery. To isolate the fly’s genome from the parasite’s, Clark fed the flies a simple antibiotic, killing the Wolbachia. To confirm the ananassae flies were indeed cured of the Wolbachia, Clark tested a few samples of DNA for the presence of several Wolbachia genes.
To his dismay, he found them.
“For several months, I thought I was just failing,” says Clark.
“I kept administering antibiotics, but every single Wolbachia gene I tested for was still there. I started thinking maybe the strain had grown antibiotic resistance. After months of this I finally went back and looked at the tissue again, and there was no Wolbachia there at all.”
Clark had cured the fly of the parasite, but a copy of the parasite’s genome was still present in the fly’s genome. Clark was able to see that Wolbachia genes were present on the second chromosome of the insect.
Clark confirmed that the Wolbachia genes are inherited like “normal” insect genes in the chromosomes, and Dunning-Hotopp showed that some of the genes are “transcribed” in uninfected flies, meaning that copies of the gene sequence are made in cells that could be used to make Wolbachia proteins.
Werren doesn’t believe that the Wolbachia “intentionally” insert their genes into the hosts. Rather, it is a consequence of cells routinely repairing their damaged DNA. As cells go about their regular business, they can accidentally absorb bits of DNA into their nuclei, often sewing those foreign genes into their own DNA. But integrating an entire genome was definitely an unexpected find.
Werren and Clark are now looking further into the huge insert found in the fruit fly, and whether it is providing a benefit.
“The chance that a chunk of DNA of this magnitude is totally neutral, I think, is pretty small, so the implication is that it has imparted of some selective advantage to the host,” says Werren.
“The question is, are these foreign genes providing new functions for the host? This is something we need to figure out.”
Evolutionary biologists will certainly take note of this discovery, but scientists conducting genome — sequencing projects around the world also may have to readjust their thinking.
Before this study, geneticists knew of examples where genes from a parasite had crossed into the host, but such an event was considered a rare anomaly except in very simple organisms. Bacterial DNA is very conspicuous in its structure, so if scientists sequencing a nematode genome, for example, come across bacterial DNA, they would likely discard it, reasonably assuming that it was merely contamination — perhaps a bit of bacteria in the gut of the animal, or on its skin.
But those genes may not be contamination. They may very well be in the host’s own genome. This is exactly what happened with the original sequencing of the genome of the ananassae fruit fly — the huge Wolbachia insert was discarded from the final assembly, despite the fact that it is part of the fly’s genome.
In the early days of the Human Genome Project, some studies appeared to show bacterial DNA residing in our own genome, but those were shown indeed to be caused by contamination. Wolbachia is not known to infect any vertebrates such as humans.
“Such transfers have happened before in the distant past” notes Werren.
“In our very own cells and those of nearly all plants and animals are mitochondria, special structures responsible for generating most of our cells’ supply of chemical energy. These were once bacteria that lived inside cells, much like Wolbachia does today. Mitochondria still retain their own, albeit tiny, DNA, and most of the genes moved into the nucleus in the very distant past. Like Wolbachia, they have passively exchanged DNA with their host cells. It’s possible Wolbachia may follow in the path of mitochondria, eventually becoming a necessary and useful part of a cell.”
“In a way, Wolbachia could be the next mitochondria,” says Werren.
“A hundred million years from now, everyone may have a Wolbachia organelle.”
“Well, not us,” he laughs.
“We’ll be long gone, but Wolbachia will still be around.”
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ZenMaster
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Friday, 31 August 2007
One species' entire genome discovered inside another's
Wednesday, 29 August 2007
Over-sized mice get even bigger!
'Mighty mice' made mightier
Wednesday, 29 August 2007
The Johns Hopkins scientist who first showed that the absence of the protein myostatin leads to oversized muscles in mice and men has now found a second protein, follistatin, whose overproduction in mice lacking myostatin doubles the muscle-building effect.
Results of Se-Jin Lee’s new study, appearing on August 29 in the online, open-access journal PLoS ONE, show that while mice that lack the gene that makes myostatin have roughly twice the amount of body muscle as normal, mice without myostatin that also overproduce follistatin have about four times as much muscle as normal mice.
Lee, M.D., Ph.D., a professor of molecular biology and genetics, says that this added muscle increase could significantly boost research efforts to “beef up” livestock or promote muscle growth in patients with muscular dystrophy and other wasting diseases.
Specifically, Lee first discovered that follistatin was capable of blocking myostatin activity in muscle cells grown under lab conditions. When he gave it to normal mice, the rodents bulked up, just as would happen if the myostatin gene in these animals was turned off. He then genetically engineered a mouse that both lacked myostatin and made extra follistatin. If follistatin was increasing muscle growth solely by blocking myostatin, then Lee surmised that follistatin would have no added effect in the absence of myostatin.
“To my surprise and delight, there was an additive effect,” said Lee, who notes these muscular mice averaged a 117 percent increase in muscle fibre size and a 73 percent increase in total muscle fibres compared to normal mice.
“These findings show that the capacity for increasing muscle growth by targeting these pathways is much more extensive than we have appreciated,” adds Lee.
“Now we’ll search for other players that cooperate with myostatin, so we can tap the full potential for enhancing muscle growth for clinical applications.”
Lee adds that this issue is of particular significance, as most agents targeting this pathway, including one drug being currently tested in a muscular dystrophy clinical trial, have been designed to block only myostatin and not other related proteins.
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ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html
Monday, 27 August 2007
hESC help rat hearts repair
Human derived stem cells can repair rat hearts damaged by heart attack Monday, 27 August 2007 When human heart muscle cells derived from embryonic stem cells are implanted into a rat after a heart attack, they can help rebuild the animal's heart muscle and improve function of the organ, scientists report in the September issue of Nature Biotechnology. The researchers also developed a new process that greatly improves how stem cells are turned into heart muscle cells and then survive after being implanted in the damaged rat heart. The findings suggest that stem-cell-based treatments might one day help people suffering from heart disease, the leading cause of death in most of the world. The study was conducted by researchers at the University of Washington School of Medicine in Seattle and at Geron Corp. in Menlo Park, California. The scientists set out to tackle two of the main challenges to treating damaged hearts with stem cells: the creation of cardiac cells from embryonic stem cells, and the survival of those cells once they are implanted in a damaged heart. "Past attempts at treating infarcted hearts with stem cells have shown promise, but they have really been hampered by these challenges," explained Dr. Chuck Murry, director of the Center for Cardiovascular Biology in the UW Institute for Stem Cell and Regenerative Medicine, and corresponding author on the study. "This method we developed goes a long way towards solving both of those problems. We got stem cells to differentiate into mostly cardiac muscle cells, and then got those cardiac cells to survive and thrive in the damaged rat heart." Embryonic stem cells can differentiate, or turn into, any type of cell found in the body. But researchers had struggled to get stem cells to differentiate into just cardiomyocytes, or heart muscle cells — most previous efforts resulted in cell preparations in which only a fraction of 1 percent of the differentiated cells were cardiac muscle cells. By treating the stem cells with two growth factors, or growth-encouraging proteins, and then purifying the cells, they were able to turn about 90 percent of stem cells into cardiomyocytes. The researchers dealt with the other big challenge of stem cell death by implanting the cells along with a cocktail of compounds aimed at helping them grow. The cocktail included a growth "matrix" — a sort of scaffolding for the cells to latch on to as they grow — and drugs that block processes related to cell death. When using the pro-growth cocktail, the success rate of heart muscle grafts improved drastically: 100 percent of rat hearts showed successful tissue grafts, compared to only 18 percent in grafts without the cocktail. "The problem of cell death is pretty common in stem-cell treatments," Murry explained. "When we try to regenerate with liquid tissues, like blood or bone marrow, we're pretty good at it, but we haven't been very successful with solid tissues like skeletal muscle, brain tissue, or heart muscle. This is one of the most successful attempts so far using cells to repair solid tissues — every one of the treated hearts had a well-developed tissue graft." When the researchers followed up on the stem-cell treatment by taking images of the rat hearts, they found that the grafts helped thicken the walls that normally stretch out after a heart attack and cause the heart to weaken. The thickened walls were also associated with more vigorous contraction. "We found that the grafts didn't just survive in the rat hearts — they also helped improve the function of the damaged heart," said Dr. Michael Laflamme, UW assistant professor of pathology and the lead author of the study. "That's very important, because one of the major problems for people suffering a myocardial infarction is that the heart is damaged and doesn't pump blood nearly as well. This sort of treatment could help the heart rebound from an infarction and retain more of its function afterwards." The next step in studying stem-cell treatments for the heart is to conduct similar experiments in large animals, like pigs or sheep, while further refining the treatment in rats. Early human clinical trials could begin in about two years, Murry said. ......... ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html
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